A Mouse Model of Multiple System Atrophy: Bench to Bedside

Abstract

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson’s disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. MSA has no efficient therapy to date. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.

α-Synuclein Strains and Their Relevance to Parkinson’s Disease, Multiple System Atrophy, and Dementia with Lewy Bodies

“…Using ultracentrifugation on brain homogenates, the authors showed that only fractions enriched in Sarkosyl-insoluble αSyn aggregates were seedingcompetent, with MSA fractions being 100 times more potent than PD homogenates to induce aggregation in a cell model. It should be noted, though, that in these studies, MSArelated αSyn fibrils injection did not faithfully recapitulate the MSA pathology, affecting primarily neurons [48]. This is not true for non-human primates, where injections of GCI induce an MSA-like pathology with loss of oligodendrocytes and gliosis [49].…”

A New Look at Animal Models of Neurological Disorders

“…Extensive animal studies are beginning to clarify the contribution of various forms of alpha-synuclein to the pathology (Peelaerts and Baekelandt [5]), to elucidate the mechanisms of disease spread first suspected on the basis of human postmortem pathological studies (Pinto-Costa et al [6]), and to model previously neglected non-motor aspects of Parkinson's disease (as reviewed by Richter et al [7]). Furthermore, Stefanova [8] shows how genetic manipulations in mice led to the generation of a model of Multiple Systems Atrophy, a rare disease in which alphasynuclein surprisingly accumulates in glial cells rather than in neurons. Each of these models contributes to a better understanding of synucleopathies, and some provide meaningful tools for the preclinical testing of novel therapies [7,8].…”

“…Furthermore, Stefanova [8] shows how genetic manipulations in mice led to the generation of a model of Multiple Systems Atrophy, a rare disease in which alphasynuclein surprisingly accumulates in glial cells rather than in neurons. Each of these models contributes to a better understanding of synucleopathies, and some provide meaningful tools for the preclinical testing of novel therapies [7,8]. In the absence of a neuroprotective treatment that has been validated in the clinic, their predictability remains uncertain.…”